Related Terms

• ADAMTS2 gene, arthrochalasia type, COL1A1 gene, COL1A2 gene, COL3A1 gene, COL5A1 gene, COL5A2 gene, classic type, collagen, dermatosparaxis type, E-D syndrome, EDS, hypermobility type, kyphoscoliosis type, PLOD1 gene, TNXB gene, vascular type.

Background

• Ehlers-Danlos syndrome (EDS) refers to a group of rare genetic disorders that affect the connective tissues, which provide support to the skin, bones, blood vessels, and other organs of the body. EDS formerly was broken down into more than 10 distinct types of the disease but has been consolidated into six categories.

• The six categories are arthrochalasia, classic, dermatosparaxis, hypermobility, kyphoscoliosis, and vascular. While other forms of the disease do exist, they are extremely rare and are not considered distinct entities.

• Symptoms of EDS may range from mild to severe and life threatening. All types of EDS affect the joints, and many also affect the skin. Almost all forms of the disease are characterized by hypermobility of the joints, which means an abnormally wide range of motion.

• The hypermobility and classic forms of EDS are the most common. Other types are extremely rare. There are about 30 known cases of the arthrochalasia type and about 60 of the kyphoscoliosis type. Only about 12 infants are known to have had the dermatosparaxis type.

• The prevalence of all types of EDS worldwide is about 1 in 400,000 people. Of people with EDS, the hypermobility type occurs in about 1 in 10,000-15,000 people, while the classic type occurs in about 1 in 20,000-40,000 people. The vascular type, which is extremely rare, occurs in about 1 in 250,000 people with EDS. EDS appears to affect males and females in equal numbers. Some research indicates that EDS may be more common in Caucasians than in other groups.

• EDS is caused by mutations or defects in the ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes. Some of these genes provide instructions for making proteins used to make collagen, the primary component of connective tissues. Others provide instructions for making proteins that interact with collagen. The genetic mutations that cause EDS affect the proper structure and function of collagen, which can weaken connective tissues and cause symptoms.

• EDS is inherited, or passed down among family members. The pattern of inheritance varies based on the type of EDS. All types of EDS may also occur in people with no family history of the disorder, as the result of a spontaneous genetic mutation in the sperm, egg cells, or developing embryo.

• Most people with EDS can live a fairly normal life. People with vascular EDS (type 4) often have a shorter than normal lifespan because of complications ranging from a collapsed lung to severe blood vessel problems. Cognitive function tends to remain unaffected in EDS. There is no cure for EDS. Instead, treatment involves managing symptoms and learning how to protect the joints and prevent injuries.

Risk Factors

• Ehlers-Danlos syndrome (EDS) is a group of rare genetic disorders. A family history of EDS is a risk factor in some cases. Different forms of EDS result from defects in different genes that may arise through autosomal dominant, autosomal recessive, or X-linked inheritance patterns.

Causes

• Genetic mutations: Ehlers-Danlos syndrome (EDS) is caused by mutations or defects in a variety of genes, including the ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, PLOD1, and TNXB genes. The COL1A1, COL1A2, COL3A1, COL5A1, and COL5A genes provide instructions for making the proteins that create different types of collagen, which strengthens, holds together, and provides elasticity in the cells of the body, including the skin, joints, and blood vessels. The ADAMTS2, PLOD1, and TNXB genes provide instructions for making proteins that interact with collagen. When any of these genes is defective, the structure and function of collagen is affected, which causes the skin, bone, and other connective tissue symptoms seen in EDS.

• Autosomal dominant inheritance: The arthrochalasia, classic, hypermobility, and vascular types of EDS follow an autosomal dominant pattern of inheritance, meaning that only one copy of the defective gene is necessary for the disease to appear. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.

• Autosomal recessive inheritance: The dermatosparaxis and kyphoscoliosis types and some cases of the classic and hypermobility types of EDS follow an autosomal recessive pattern of inheritance, meaning that an individual must inherit two copies of the defective gene, one from each parent, in order for the disease to appear. Individuals who inherit only one copy of the defective gene generally have no symptoms and are called carriers, because they can pass on the disorder to their children.

• If one parent is a carrier, then each child has a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of not inheriting either defective gene.

• X-linked recessive inheritance: One type of EDS, formerly known as type V but not classified in the new system, may follow an X-linked recessive pattern of inheritance. Females have two copies of the X chromosome, while males have one X and one Y chromosome. Males inherit an X chromosome from the mother and a Y chromosome from the father, so a male can inherit an X-linked gene only from the mother. Therefore, a female needs to inherit two copies of the defective gene to develop this form of EDS, while males need to inherit only one copy of the defective gene to develop the condition. If a woman carries the defective gene that causes this type of EDS, there is a 50% chance that her sons will inherit the disorder and a 50% chance that her daughters will inherit only one defective copy and thus be carriers of the gene. If a man carries the defective gene that causes this type of EDS, all of his daughters would be carriers, but none of his sons would be affected or be a carrier.

• Random occurrence: In some cases, EDS will be present in an individual with no family history of the disorder. This may occur as the result of a spontaneous genetic mutation in the egg, sperm cells, or developing embryo.

Types of the Disease

• General: Ehlers-Danlos syndrome (EDS) formerly was broken down into more than 10 distinct types of the disease. However, researchers have recently consolidated the different forms into six categories, which are arthrochalasia, classic, dermatosparaxis, hypermobility, kyphoscoliosis, and vascular. Individual cases may fit into more than one category of disease, and overlap is common.

• Arthrochalasia type: Formerly known as type VII EDS, the arthrochalasia type of EDS is inherited as an autosomal dominant trait. Only about 30 cases have been reported. Signs and symptoms of this type include very loose joints and dislocation of both hips that is present at birth; stretchy, fragile skin that is prone to bruising and scarring; early-onset arthritis; and increased risk of bone loss and fracture. People with this type of EDS may have short stature.

• Classic type: Formerly known as EDS types I and II, the classic type may be inherited as an autosomal dominant or autosomal recessive trait and is the best described of all the types. This type affects approximately 2-5 in 100,000 people and may be caused by mutations in the COL5A1, COL5A2, COL1A2, or TNXB genes. These genes provide instructions for making components of collagen. When inherited as an autosomal dominant trait, the classic type of EDS appears to be caused by mutations in the COL5A1 or COL5A2 gene. It is estimated that about half of cases of the classic form of the disease are caused by mutations in the COL5A1 gene. Signs and symptoms of this type of EDS include loose joints, which are prone to dislocation and may delay the development of gross motor skills, especially when a child starts to walk; highly elastic, velvety skin; fragile skin that bruises or tears easily; slow and poor wound healing, leading to scarring; noncancerous fibrous growths on pressure areas such as elbows and knees; fatty growths on the shins and forearms; hernias; and heart valve problems, including mitral valve prolapse.

• Dermatosparaxis type: Formerly known as type VII EDS, the dermatosparaxis type of EDS is inherited as an autosomal recessive trait. This type of EDS is also particularly rare, with only 10 cases reported in the scientific literature. Signs and symptoms of this type of EDS include extremely fragile and sagging skin; loose joints, which may delay the development of motor skills in children; short stature; delayed closure of the fontanelles, the soft areas at the top of a baby's head; characteristic facial appearance with swollen eyelids and a bluish tinge to the whites of the eyes; umbilical hernia; and short fingers.

• Hypermobility type: Formerly known as type III EDS, the hypermobility type may be inherited as an autosomal dominant or recessive trait. This type of EDS affects 1 in 10,000-15,000 people. Signs and symptoms of this subtype include loose, unstable joints; soft, velvety skin; chronic degenerative joint disease; advanced premature osteoarthritis with chronic pain; and heart valve problems, such as mitral valve prolapse. This type may also feature gum disease.

• Kyphoscoliosis type: Formerly known as type VI EDS, the kyphoscoliosis type is inherited as an autosomal recessive trait. As another rare form of EDS, only 60 cases of the kyphoscoliosis type have been reported. This type of EDS is associated with progressive abnormal curvature of the spine, which may affect breathing. People with this type of EDS may also have more serious eye problems, including glaucoma (increased pressure in the eye), discoloration of the whites of the eyes, and a detached retina, which is when the retina is pulled away from its normal position in the back of the eye. The retina sends visual images from the eye to the brain through the optic nerve. Individuals with this type of EDS also are at increased risk of rupture of the medium-sized arteries.

• Vascular type: Formerly known as type IV EDS, the vascular type is inherited as an autosomal dominant trait. This type of EDS affects approximately 1 in 100,000 people and is the most severe, with past studies having placed life expectancy at around 48 years. The vascular type of EDS is associated with potentially life-threatening ruptures of the blood vessels, lung problems, and internal organ damage. Individuals with this type of EDS may have low body weight and short stature. Surgery can be extremely dangerous for people with this type of EDS.

• Other types of EDS: The types of EDS formerly known as types V, VIII, IX, X, and XI are extremely rare and were not included in the updated classification.

Signs and Symptoms

• General: In Ehlers-Danlos syndrome (EDS), genetic mutations or defects disrupt the production of collagen, the protein that binds, strengthens, and provides elasticity to the cells and tissues in the body. Symptoms and severity may vary depending on the type of EDS. Symptoms affecting the joints and skin, which are present in all types of the disease, tend to be apparent early in life. Other symptoms may not be recognized until later in life. Exactly when these symptoms occur may depend on the type of EDS an individual has.

• Blood vessels: In people with EDS, the blood vessels may be extremely fragile, thin, and easily damaged. This fragility can cause a ruptured artery, or aneurysm, which can occur when a blood vessel develops a balloon-like bulge that can burst and result in death.

• Eyes: People with EDS may be nearsighted. In some individuals, visual impairment can be severe.

• Joints: The joints of EDS patients tend to be abnormally flexible, "double-jointed," and loose. They may easily become dislocated and painful, especially in the shoulders, knees, hips, collarbone, and jaw.

• Skin: Skin may be velvety, doughy, loose, thin, easily bruised, and abnormally elastic or "stretchy." It may also be extremely fragile and scar easily. A classic sign of EDS is "cigarette paper scars," which widen over time as wounds repeatedly break open. Wounds may take an abnormally long time to heal. Small, harmless bumps may also be present under the skin.

• Other: Some people with EDS may have weak muscles, which may result in frequent falls, difficulty walking, and poor body control. Others may have early-onset arthritis, dental problems, blood vessel disease, or easily damaged internal organs. People with the kyphoscoliosis type of EDS have a progressive abnormal curvature of the spine.

Diagnosis

• General: In Ehlers-Danlos syndrome (EDS), genetic mutations or defects disrupt the production of collagen, the protein that binds, strengthens, and provides elasticity to the cells and tissues in the body. Symptoms affecting the joints and skin, which are present in all types of the disease, tend to be apparent early in life, while other symptoms may not be recognized until later. EDS is usually diagnosed in young adults. Typical signs and symptoms of EDS include skin that is especially stretchy or fragile; hernias; abnormal wound healing; scars that stretch over time; flexible joints that extend beyond the normal range of movement; dislocations of the shoulder, knee, fingers, hip, wrist and collarbone; muscle weakness; delayed motor development; easy bruising; heart problems, such as mitral valve prolapse, aortic root dilatation, and spontaneous rupture of large arteries; and a family history of ruptured uterus, colon, or brain aneurysm.

• Physical exam: To diagnose Ehlers-Danlos syndrome, a complete physical examination and medical and family history will be taken. Extremely loose joints, fragile skin, and a family history of EDS may help lead to a diagnosis.

• Genetic testing: DNA testing is available for the classic, vascular, kyphoscoliosis, and arthrochalasis types of EDS. Prenatal DNA testing and preimplantation genetic diagnosis, a method that tests embryos developed by in vitro fertilization, may be available for families in which the disease-causing mutation has been identified.

• Urine testing: A urine test is available to help identify kyphoscoliosis-type EDS. The test measures levels of an enzyme produced by the gene associated with this EDS type. Abnormal levels of this enzyme typically indicate this form of EDS.

• Skin biopsy: In this test, a small sample of skin is removed and examined under a microscope. Such a test may reveal abnormalities in the skin's collagen fibers. The vascular type of EDS can be diagnosed by analyzing the collagen produced by skin cells.

• Imaging: A heart ultrasound can be performed to check for mitral valve prolapse, a heart condition that can occur with the classic and hypermobility EDS subtypes. A heart ultrasound provides real-time images of the heart in motion and can help identify abnormalities in the heart muscle and valves and find any fluid that may surround the heart.

Complications

• General: Most people with Ehlers-Danlos syndrome (EDS) live a relatively normal life, although there may be restrictions to their level of physical activity. Individuals with the vascular type of EDS are at risk of serious complications, including rupture of major blood vessels or organs, such as the intestines or uterus. These complications can be fatal. About one in four people with the vascular type of EDS develop a significant health problem by age 20, and more than 80% develop complications by age 40; the median age of death is 48 years. An individual with kyphoscoliosis-type EDS may be at increased risk of eye problems and may need to be monitored by an eye specialist. Some people with Ehlers-Danlos syndrome may develop osteoporosis.

• Arthritis: The mutation that results in a lack of collagen may cause some people with EDS to develop arthritis, because of repetitive injury to the joints. Individuals with EDS are advised not to overextend or lock their joints, as this can lead to chronic arthritis.

• Breathing problems: Some people with EDS, especially those with the kyphoscoliosis type, may have breathing problems. This is especially evident if the individual suffers from scoliosis (an abnormal sideways curvature of the spine) or kyphosis (forward curvature of the spine) that is severe enough to press on the lungs and flex the windpipe.

• Dental problems: Some people with EDS, especially those with the hypermobility type, may be prone to gum and dental disease.

• Pain: People with EDS may have pain related to dislocation of joints, easy tearing of the skin, and abnormal curvature of the spine.

• Sudden death: Some people with EDS, especially those with the vascular type, may be at risk for sudden death from a spontaneous rupture in a major blood vessel or internal organ or from a stroke.

• Visual impairment: Some people with EDS, especially those with the kyphoscoliosis type, may have mild-to-severe visual impairment. Eye problems include nearsightedness, glaucoma (increased pressure in the eye), discoloration of the whites of the eyes, and a detached retina, which occurs when the retina is pulled away from its normal position in the back of the eye. The retina sends visual images from the eye to the brain through the optic nerve.

Treatment

• General: There is no cure for Ehlers-Danlos syndrome (EDS). Instead, treatment focuses on the alleviation of symptoms and prevention of complications. People with EDS should be regularly seen by an orthopedist, ophthalmologist, physician, and dermatologist, depending on individual needs.

• Treatment strategies vary based on the type and severity of EDS, and great care should be taken to avoid injury, including injury from surgery.

• Activity restrictions: Some people with EDS, especially those with the vascular or kyphoscoliosis types, should avoid potentially dangerous activities such as contact sports. Certain activities, such as playing a musical instrument, may also need to be avoided because of increased pressure in the brain.

• Collagen replacement therapy: The mutation that results in a lack of collagen can cause some people with EDS to develop arthritis from repetitive injury to the joints. Collagen, a naturally occurring fibrous protein found in both humans and animals, provides structural support for bones, skin, tendons, ligaments, and blood vessels and is the most abundant protein in the body. Collagen replacement therapy can help build up collagen levels in the body. However, this has not been accepted as a treatment for arthritis.

• Corrective lenses: Nearsightedness can be corrected with glasses or contact lenses.

• Dental care: Patients with EDS must practice good preventive dental care, including regular flossing, teeth brushing, and visits to the dentist. Enlarged gums can be reduced by a procedure called gingivectomy, which removes and reshapes loose, diseased gum tissue to remove pockets between the teeth and gums. This procedure may be needed repeatedly, as excess tissue grows back. Diligent oral care can reduce the need for repeat gingivectomy.

• Exercise therapy: Certain exercises, such as swimming, may improve muscle strength without placing undue stress on the joints. A qualified healthcare professional can help identify ideal activities for individuals with EDS.

• Pain relievers: Noninflammatory pain relievers, such as nonsteroidal anti-inflammatory drugs (NSAIDs), can be used to reduce inflammation and pain associated with arthritis. Some NSAIDs include Advil®, Motrin®, Aleve®, and newer formulations such as Vioxx® and Celebrex®, which are COX-2 inhibitors and also reduce inflammation but were developed to have fewer side effects than NSAIDs. NSAIDs are safest when low doses are taken for brief periods. Side effects most commonly occur with large doses over a prolonged time of months or years. Some side effects are mild and go away on their own or after the dose is reduced. Others may be more serious and need medical attention. Common side effects of NSAIDs include stomach pain and heartburn; stomach ulcers; an increase in bleeding tendency, especially with aspirin; headaches and dizziness; and ringing in the ears from certain NSAIDs, including aspirin. Allergic reactions such as rashes, wheezing, and throat swelling; liver or kidney problems; high blood pressure; and leg swelling can usually be eliminated by decreasing the dose.

• Physical therapy: Physical therapy can include an exercise program to strengthen the muscles, which in turn will help stabilize the joints. In general, people with EDS need to avoid activities that put pressure on locked joints, such as weightlifting.

• Plastic surgery: People with EDS may choose to have plastic surgery to improve the appearance of scars caused by recurrent wound opening.

• Self-management: People with EDS should be educated on how to make choices that help to avoid injury, reduce pain, and optimize quality of life. Education should encourage people with EDS to avoid activities that cause locking or overextension of joints, and to create a safe environment that may include placing nonslip pads under rugs, wearing protective gear such as knee pads, and using adaptive equipment to help with activities of daily living. People with EDS should also be encouraged to avoid excessive sun exposure, which may worsen skin conditions.

• Sun protection: Premature aging from sun exposure is a risk for all people, but particularly for those with EDS. Sunscreen with a sun protection factor (SPF) of at least 15 should be applied to exposed skin every day.

• Surgery: Dislocated joints and bone fractures may require surgical correction. Surgery may also be required to correct scoliosis (an abnormal sideways curvature of the spine) or kyphosis (forward curvature of the spine). A procedure called rodding includes the insertion of metal rods to stabilize the spine. The unique needs of people with EDS may cause surgeons to choose stapes or tape to close wounds rather than stitches, which may damage the skin and cause bleeding, pain, and scarring.

• Vitamin C: People with the kyphoscoliosis-type of EDS may benefit from taking vitamin C supplements, although this treatment has not been established as an accepted therapy. Most people with Ehlers-Danlos syndrome live a relatively normal life, although there may be restrictions on the level and type of physical activity. Individuals with the vascular type of EDS are at risk of serious complications, including rupture of major blood vessels or organs, such as the intestines or uterus. These complications can be fatal. About one in four people with the vascular type EDS develop a significant health problem by age 20, and more than 80% develop complications by age 40; the median age of death is 48 years.

Integrative Therapies

• Currently there is a lack of scientific evidence on the use of integrative therapies for the treatment or prevention of Ehlers-Danlos syndrome (EDS).

Prevention

• General: Because Ehlers-Danlos syndrome (EDS) is inherited, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of EDS.

• Genetic testing and counseling: Individuals who have EDS may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals with a family history of EDS may meet with a genetic counselor to determine whether they carry the defective genes. Carriers can be determined through detailed family histories or genetic testing.

• Known carriers of EDS may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS), all of which determine the likelihood of a child inheriting the disorder prior to conception or while in the womb.

• Preimplantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective genes, and only the embryos that are not affected may be selected for implantation. Because EDS can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

1. Demirogullari B, Karabulut R, Demirtola A, et al. A novel mutation in the vascular Ehlers-Danlos syndrome: a case presenting with colonic perforations. J Pediatr Surg. 2006;41(8):e27-30. View Abstract

2. EDS Today. www.edstoday.org.

3. Ehlers-Danlos National Foundation (EDNF) www.ednf.org.

4. Lane D. Anaesthetic implications of vascular type Ehlers-Danlos syndrome. Anaesth Intensive Care. 2006;34(4):501-5. View Abstract

5. Lumley MA, Jordan M, Rubenstein R, et al. Psychosocial functioning in the Ehlers-Danlos syndrome. Am J Med Genet. 1994;53(2):149-52. View Abstract

6. Mao JR, Bristow J. The Ehlers-Danlos syndrome: on beyond collagens. J Clin Invest. 2001;107(9):1063-9. View Abstract

7. Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com.

8. NIH/National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse. www.niams.nih.gov.

9. Schalkwijk J, Zweers MC, Steijlen PM, et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345(16):1167-75. View Abstract

10. Schwarze U, Atkinson M, Hoffman GG, et al. Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II). Am J Hum Genet. 2000;66(6):1757-65. View Abstract

11. Tsipouras P, Byers PH, Schwartz RC, et al. Ehlers-Danlos syndrome type IV: cosegregation of the phenotype to a COL3A1 allele of type III procollagen. Hum Genet. 1986;74(1):41-6. View Abstract

12. Yassin OM, Rihani FB. Multiple developmental dental anomalies and hypermobility type Ehlers-Danlos syndrome. J Clin Pediatr Dent. 2006;30 (4):337-41. View Abstract

13. Yigal A, Tal H, Nurit H, et al. Thromboembolic renal infarction due to a renal artery aneurysm in a patient with Ehlers-Danlos syndrome type IV. Eur J Intern Med. 2006;17(5):377-9. View Abstract